Taking on the resistance

The looming disaster of antimicrobial resistance is well known one…but what are we doing about this ‘catastrophic threat’? Tim Sandle delves into the Five Year Antimicrobial Resistance Strategy to find out Since the introduction of penicillin in the 1940s antimicrobial medicines, such as antibiotics, have become essential for the treatment of many microbial infections in humans and animals. Antibiotics have a variety of uses including treating and preventing infections and reducing the risk of potentially life threatening complications in surgery, chemotherapy and transplantation. With the use of such medicines, a phenomenon called ‘antibiotic resistance’ occurs. Antibiotic resistance is a form of drug resistance whereby some sub-populations of a microorganism are able to survive after exposure to one or more antibiotics. In the last two decades, the rate at which bacteria are becoming resistant to current antibiotic treatments has substantially increased. This trend is threatening the ability of medical staff to carry out routine operations or transplants in the future. This has been compounded not only by microorganisms that are resistant to one antimicrobial or another, but due to the rise of multi-drug resistant microorganisms (the so-termed ‘super bugs’). Prominent examples include MRSA (methicillin-resistant Staphylococcus aureus), VISA (vancomycin-intermediate S. aureus), VRSA (vancomycin-resistant S. aureus), ESBL (Extended spectrum beta-lactamase), VRE (vancomycin-resistant Enterococcus) and MRAB (multidrug-resistant Acinetobacter baumannii). To select some global examples to illustrate the concern with resistance, more than 25,000 Europeans, just under 100,000 Americans and around 80,000 Chinese die each year as a direct consequence of a drug-resistant infections¹. There are also ramifications for existing treatments. For example, around 40 years ago, people with cystic fibrosis generally died within their first decade of life. The median life expectancy is now over 50 years. As set out by Plummer & Wildman², “One of the major reasons for this increase in survival is the mounting use of antibiotics to treat chest exacerbations caused by bacterial infections.” As a result, if these antibiotics were no longer able to treat such infections, the life expectancy of cystic fibrosis patients would be likely to fall substantially. The primary reason for the spread of antibiotic resistances stems from the overuse of the medicines. Whilst there were low levels of pre-existing antibiotic-resistant bacteria before the widespread use of antibiotics, evolutionary pressure from their use has played a role in the development of multidrug resistance varieties and the spread of resistance between bacterial species. Other practices contributing towards resistance include antibiotic use in livestock feed. There are also economic consequences. This was a major focus of the World Economic Forum Global Risks 2013 report published in February. In 2009, the European Centre for Disease Control (ECDC) estimated that antimicrobial resistance costs the EU approximately €1.5 billion in healthcare expenses and lost productivity each year, while the cost to the US is estimated to between $21 billion and $34 billion³. One identified need is the requirement for new antibiotics; for this development, the role of pharmaceutical microbiologist is important. A significant hurdle in relation to new antibiotics is the long-lead times and relatively low return-on-investment, which can act as a disincentive for pharmaceutical organisations to develop new medicines. Moreover, the problem of resistance means that new antibiotics have a relatively short useful lifespan (which additionally affects the return on investment in relation to new antibiotic development). As step towards taking action for the UK health service and as a step towards seeking global action, the British government have released a new strategy document⁴. The strategy document was triggered, in part by, a series of public statements made by the UK Chief Medical officer in March 2013, Professor Dame Sally Davies. Professor Davies declared that antibiotic resistance is a 'catastrophic threat' across the globe. She went onto say that: “We haven't as a society globally incentivised making antibiotics. It's quite simple – if they make something to treat high blood pressure or diabetes and it works, we will use it on our patients every day. Whereas antibiotics will only be used for a week or two when they're needed, and then they have a limited life span because of resistance developing anyway." ⁵ In response the British government released a strategic plan ‘Five Year Antimicrobial Resistance Strategy’⁶. For the preparation of the strategy document, more than 130 organisations contributed during the consultation process. The Five Year Antimicrobial Resistance Strategy outlines that steps are being taken to:

1. Improve how we prevent and manage infections in people and in animals; including through better hygiene and monitoring of bacteria in medical and community settings, and through better farming practices.
2. Improve education and training around the prescribing of antibiotics to reduce inappropriate usage and make sure patients get the right antibiotics, at the right time and for the right duration.
3. Collect better data on the resistance of bugs so we can track them more effectively, find the most resistant bacteria and step in earlier where there is resistance to antibiotics.
4. Provide funding of up to £4 million to set up a new National Institute of Health Research (NIHR) Health Protection Research Unit which will focus on AMR and healthcare associated infections. In recognition of the importance of quick action, the NIHR is also running a themed research call to encourage AMR research across a range of areas.
5. Explore ways to encourage the development of new antibiotics, rapid diagnostics and other treatments by working with industry and across Government.

The analyses assume that there will not be a substantial change in the number of antimicrobials prescribed. One of the key challenges of the new UK strategy is to communicate the significance of antimicrobial resistance to all the government departments, pharmaceutical companies, hospitals, doctors, vets, patients, farmers, border officials and scientists whose combined efforts are needed to stop the increase in resistance seen over the last 50 years. The problem is not simply one of concern for the UK, as the document identifies. The strategy document calls upon a wide range of health and Government organisations to engage with and contribute to this work. It also highlights the importance of working with the farming, food, retail and pharmaceutical sectors, as well as the academic community and professional bodies. Here the strategy document places a focus upon the World Health Organisation (WHO) to take the growing threat seriously and creative a system of incentives that will encourage innovation and investment in the field of antibiotic research and development. In line with the British document, the European Union are preparing a similar response. Due to growing concerns about the overuse of antibiotics contributing to the global public health threat of drug-resistant bacterial infections in humans, the European Medicines Agency (EMA) has suggested a ban on the blanket use of the antibiotic colistin for farm animals, as reported by Nature⁷.  The argument against this practice is that animals fed low-dose antibiotics not only propagate antibiotic resistant bacteria, but practices also spread these resistant strains to farmers, their families, community residents, and ultimately, hospitalised patients. The European Commission is developing its own ‘Action Plan Against the rising threats from Antimicrobial Resistance’, which will be finalised at the end of 2014⁸. The report states that: “A substantial reinforcement of current measures in place together with a new set of rigorous measures are therefore needed in order to reduce the pressure of using antimicrobials and to prevent the further spread of resistance and preserve the ability to combat microbial infections.” In summary, the strategic direction outlined is that, firstly, we need to conserve the antibiotics we have left by using them optimally (this is sometimes referred to as ‘antimicrobial stewardship’). Secondly, the process of developing new antimicrobials and new technologies to allow quicker diagnosis and facilitate targeted treatment must be accelerated. In addressing these points, the British and European documents signal that governments are taking the issue of antimicrobial resistance seriously. Whether this leads to any change, however, will only become clear through demonstrable action. References

1. Klein, E., Smith, D.L. and Laxminarayan, R.  (2007). Hospitalisations and Deaths Caused by Methicillin-Resistant Staphyloccocus aureus, United States, 1999-2005, Emerging Infectious Diseases, 13 (2),  Centers for Disease Control and Preventions (CDC), Atlanta GA, USA.
2. Plummer A, Wildman M. Duration of intravenous antibiotic therapy in people with cystic fibrosis. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD006682. DOI: 10.1002/14651858.CD006682.pub3
3. Spellberg, B., Blaser, M., Guidos, R. J., et al. (2011). Combating Antimicrobial Resistance: Policy Recommendations to Save Lives, Clinical Infectious Diseases: an Official Publication of the Infectious Diseases Society of America, 52:S397-428.
4. Department of Health press release “UK Antimicrobial Resistance Strategy published”: https://www.gov.uk/government/news/uk-antimicrobial-resistance-strategy-published--2
5. BBC News “Antibiotics resistance 'as big a risk as terrorism' - medical chief”: http://www.bbc.co.uk/news/health-21737844 (11th March 2013)
6. Department of Health (2013). UK Five Year Antimicrobial Resistance Strategy 2013 to 2018, Department of Health, London: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/238872/20130902_UK_5_year_AMR_strategy_FINAL.pdf
7. Nature Blogs “EU medicines regulator says no to farmers’ blanket use of antibiotic”: http://blogs.nature.com/news/2013/07/eu-medicines-regulator-says-no-to-farmers-blanket-use-of-antibiotic.html
8. European Commission (2013). Action plan against the rising threats from Antimicrobial Resistance, European Commission, Brussels: http://ec.europa.eu/dgs/health_consumer/docs/communication_amr_2011_748_en.pdf

Author Tim Sandle, Head of Microbiology at Bio Products Laboratory, Contact timsandle@btinternet.com www.pharmamicroresources.com